Adaptive designs have become popular in clinical trial and drug development. Unlike traditional trial designs, adaptive designs use accumulating data to modify the ongoing trial without undermining the integrity and validity of the trial, often incorporated with advanced mathematical modeling. As a result, adaptive designs provide a flexible and effective way to conduct clinical trials. The designs have potential advantages of improving the study power, reducing sample size and total cost, treating more patients with more effective treatments, identifying efficacious drugs for specific subgroups of patients based on their biomarker profiles, and shortening the time for drug development.
Although the benefits of adaptive clinical trials are advantageous, there are also challenges to conduct this type of flexible trials. First, the number of treatment doses in the adaptive dose-finding stage can be significantly more than traditional clinical trials. This scenario, with its potential treatment variability and additional provisioning to respond immediately to the adaptive changes, can inherently increase, by large amount, the quantities of study drug needed. For example, in order to shorten the clinical trial duration, an adaptive clinical trial had to prepare clinical drug supply by assuming all the patients in the trial will receive all different doses (total quantity of clinical supply=total number of patients×total number of different clinical dosages), which led to significant material wastage. Second, the study blinding for different dosages may become more complex when conducting adaptive clinical trials. Clinical trials of new drugs provide critical data on the drug's effectiveness, dosage requirements and possible adverse side effects. Unlike marketing strategies developed and applied to the introduction and sales of a new drug, it is desired and sometimes necessary in clinical studies to conceal or “blind” the drug to be studied. Blinding the clinical study is believed necessary to prevent bias from the participants—patients, investigators and sponsors—from comprising the results. Blinded studies can also enhance marketability of a product by more credibly demonstrating the favorable health and economic advantages, such as greater therapeutic efficacy and fewer adverse effects, when compared with a marketed drug or placebo. In addition, many governments require blinded clinical studies for approval of a new drug. (See 21 C.F.R. 314.26 and European Union's Directive 91/507/EEC). Effective blinding requires each aspect of the treatment—dosage form, packaging, labeling, dosage interval, dosage strength and dosage composition—to appear the same. That is, none of the participants to the study should be able to discern whether they are taking placebo, one or more strengths of investigational drug, or one or more strengths of comparator drug (the comparator or control drug is a marketed drug commonly used for the disease being studied). The blinding procedure is further complicated by the need to comply with all aspects of Good Manufacturing Practices (GMP) requirements. Third, the data generated in adaptive clinical trial are dynamic, there is currently no efficient way to capture the real-time clinical data and process the data for the next step of clinical trial. Patients will be dynamic members in the clinical trial. By far most of clinical trials today are led without direct information from patients as most information are gathered by human services suppliers amid patient visits. In any case, billions of individuals are as of now conveying associated individualized computing devices and billions more will be associated through wearable devices soon. This gives the chance to catch information specifically from patients in a continuous and convenient way as they enter that data on their own devices. Even better, information for non-transferable ailments, for example, hypertension and diabetes can be caught and transmitted straightforwardly through wearable medicinal sensing devices. Accordingly, the information caught will be significantly more point by point and of higher quality in this manner expanding the pace and viability of adaptive clinical trials.
In the future, clinical trial will be more precise and more personalized. Clinical trial systems will consistently facilitate all parts of the trial and investigational item progressively empowered by the Internet of Thing (IoT) base. Clinical trial systems will move into the cloud and will be able to correspond with individuals, different frameworks, devices and supplies by means of backing of standard conventions and personality administration.
Nowadays, biologic drugs account for more than half of all therapeutic drug candidates in pharmaceutical development pipelines. These biologic drugs need to be delivered in liquid or suspension formulations through the parenteral route. Drug delivery devices, including autoinjector and wearable infusors, have been widely used for delivering drugs in liquid or suspension formulations. These drug delivery devices can improve dose accuracy and ease medication preparation/administration and reduce needle injury, which results in more patient convenience and compliance. These type of devices can be powered by mechanical force, electromechanical force, powered gas or chemical reaction and so on. Meantime, these devices can, if designed properly, hide the difference in injection dose and can be a valuable tool in study blinding, while generating many different doses. Furthermore, these devices can be integrated with electronic circuits and the clinical data (dose, dosing time, etc) data can be recorded and communicated using embedded internet communication technology (for example, Bluetooth communication) for better scientific evaluation during the clinical trial. Therefore, these drug delivery devices are useful tools to control and record treatment signals during adaptive clinical trial.
Current autoinjector or infusor devices, as the most used automatic drug delivery devices for self-administering parenteral therapeutic drugs, are mostly designed for fix dose delivery and most of them don't have the ability to be connected with internet. These present following challenge to be used for clinical trial: difficult to conduct clinical trial when different doses are evaluated, for example, during the dose-finding clinical study. These challenges often delays the introduction of autoinjector or infusor device to clinical trial until the final dose is determined. Clinical trial is the most time consuming and most expensive part of drug development. Normally, all the three phases clinical trial together can take 5-8 years and cost hundreds of million dollars. During the long time period and with the substantial spending, there are a lot of learning about the drug, for example, when how the drug is absorbed, metabolized, and what the drug effect look like. On the other hand, when the parenteral therapeutic drug is developed together with the drug delivery device, there isn't much learning about the delivery device in the early phases of clinical trial, especially human factor and usability of the device, which is highly recommended by Food and Drug Administration (FDA) (FDA draft guidance—Applying Human Factors and Usability Engineering to Optimize Medical Device Design, 2011). Also, there is often no record about when and how the drug is taken. As mentioned above, in phase I and phase II clinical trials, a very important aspect is dose-finding, which requires devices that can deliver variable dose in adaptive clinical trial. Hence, the fixed dose drug delivery device is often introduced during very late stage of clinical trial. Currently, the clinical trial for parenteral therapeutic drug start with vial/manual syringe combination. Until phase III, the more sophisticated device, such as autoinjector or infusor will be introduced and studied. Or, the more sophisticated device will be evaluated after the first launch of the drug in vial/manual syringe format. Even then, the devices used normally doesn't have data communication functions. As the results, drug developers not only under-utilize the advantage of using autoinjector or infusor device in clinical trials, but also lose the opportunity to test device human factors and usabilities as well as collecting real-time usage data during the clinical trials.
Another important aspect about clinical trial is patient's adherence to drug administration. Adherence to clinically prescribed medications is essential for all effective clinical trial. Drug actions are inherently dose and time dependent, and as a result, variable underdosing diminishes the actions of trial medications. Poor adherence to medication is one of the major sources of variance in drug response and can confuse the interpretation of therapeutic efficacy in clinical trial and more so for adaptive clinical trial due the dynamic nature of adaptive clinical trial. Therefore, adherence to clinical prescribed medication, including timely initiation and accurate implementation of the dosing regimen throughout the specified period of clinical trial, is essential for the reliable evaluation of drug treatments and for the success of clinical trials. On the other hand, radio frequency identification (RFID) and near field communication (NFC) are effective technologies for reminding user and transmitting small data sets in real time. Also, these technologies consume very little or no energy and are ideal for clinical trials to evaluate parenteral medicines because these medicines often need to be stored in refrigerated environment. Utilizing these technologies in adaptive clinical trial can certainly enhance patient's adherence to clinical medicine prescribed.
In summary, what is needed is a new method for conducting adaptive clinical studies which permits for improved development of parenteral therapeutic products with drug delivery device during clinical trials.